Combination of a c-met antagonist and an aminoheteroaryl compound for the treatment of cancer

ABSTRACT

The invention also relates to a composition comprising an antibody antagonist to c-Met and an aminoheteroaryl compound, particularly as a medicament. The present invention also comprises a pharmaceutical composition comprising said anti c-Met antibody and said aminoheteroaryl compound as combination products for simultaneous, separate or sequential use. The invention relates to the use of the composition of the invention for the treatment of cancer in a mammal.

The invention relates to a composition comprising an antibody antagonistto c-Met and an aminoheteroaryl compound, particularly as a medicament.The present invention also comprises a pharmaceutical compositioncomprising said anti c-Met antibody and said aminoheteroaryl compound ascombination products for simultaneous, separate or sequential use. Theinvention relates to the use of the composition of the invention for thetreatment of cancer in a mammal.

c-Met, is the prototypic member of a sub-family of RTKs which alsoincludes RON and SEA. The c-Met RTK family is structurally differentfrom other RTK families and is the only known high-affinity receptor forhepatocyte growth factor (HGF), also called seater factor (SF) [D. P.Bottaro et al., Science 1991, 251: 802-804; L. Naldini et al., Eur. Mol.Biol. Org. J. 1991, 10:2867-2878]. c-Met and HGF are widely expressed ina variety of tissue and their expression is normally restricted to cellsof epithelial and mesenchymal origin respectively [M. F. Di Renzo etal., Oncogene 1991, 6:1997-2003; E. Sonnenberg et al., J. Cell. Biol.1993, 123:223-235]. They are both required for normal mammaliandevelopment and have been shown to be particularly important in cellmigration, morphogenic differentiation, and organization of thethree-dimensional tubular structures as well as growth and angiogenesis[F. Baldt et al., Nature 1995, 376:768-771; C. Schmidt et al., Nature.1995:373:699-702; Tsarfaty et al., Science 1994, 263:98-101]. While thecontrolled regulation of c-Met and HGF have been shown to be importantin mammalian development, tissue maintenance and repair [Nagayama T,Nagayama M, Kohara S, Kamiguchi H, Shibuya M, Katoh Y, Itoh J, ShinoharaY., Brain Res. 2004, 5; 999(2):155-66; Tahara Y, Ido A, Yamamoto S,Miyata Y, Uto H, Hari T, Hayashi K, Tsubouchi H., J Pharmacol Exp Ther.2003, 307(1):146-51], their dysregulation is implicated in theprogression of cancers.

Aberrant signalling driven by inappropriate activation of c-Met is oneof the most frequent alteration observed in human cancers and plays acrucial role in tumorigenesis and metastasis [Birchmeier et al., Nat.Rev. Mol. Cell. Biol. 2003, 4:915-925; L. Trusolino and Comoglio P. M.,Nat. Rev. Cancer. 2002, 2(4):289-300].

c-Met activation could result from various mechanisms including i)ligand binding, ii) receptor overexpression which leads to spontaneousligand independent dimerization, or iii) mutations, mainly occurring inthe intracellular domain of c-Met, and resulting in increased andpersistent phosphorylation of c-Met or in constitutive receptoractivation [J. G. Christensen, Burrows J. and Salgia R., Cancer Letters.2005, 226:1-26].

Activated c-Met recruits signalling effectors to its multidocking sitelocated in the cytoplasm domain, resulting in the activation of severalkey signalling pathways, including Ras-MAPK, PI3K, Src and Stat3 [Gao CF, Vande Woude G F, Cell Res. 2005, 15(1):49-51; Furge K A, Zhang Y W,Vande Woude G F, Oncogene. 2000, 19(49):5582-9]. These pathways areessential for tumour cell proliferation, invasion and angiogenesis andfor evading apoptosis [Furge K A, Zhang Y W, Vande Woude G F, Oncogene,2000, 19(49):5582-9; Gu H, Neel B G, Trends Cell Biol. 2003 Mar.,13(3):122-30; Fan S, Ma Y X, Wang J A, Yuan R Q, Meng Q, Cao Y, LaterraJ J, Goldberg I D, Rosen E M, Oncogene. 2000 Apr. 27, 19(18):2212-23].In addition, a unique facet of the c-Met signalling relative to otherRTK is its reported interaction with focal adhesion complexes and nonkinase binding partners such as α6β4 integrins [Trusolino L, Bertotti A,Comoglio P M, Cell. 2001, 107:643-54], CD44v6 [Van der Voort R, Taher TE, Wielenga V J, Spaargaren M, Prevo R, Smit L, David G, Hartmann G,Gherardi E, Pals S T, J Biol Chem. 1999, 274(10):6499-506], Plexin B1 orsemaphorins [Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G,Barberis D, Tamagnone L, Comoglio P M, Nat Cell Biol. 2002, 4(9):720-4;Conrotto P, Valdembri D, Corso S, Serini G, Tamagnone L, Comoglio P M,Bussolino F, Giordano S, Blood. 2005, 105(11):4321-9; Conrotto P, CorsoS, Gamberini S, Comoglio P M, Giordano S, Oncogene. 2004, 23:5131-7]which may further add to the complexity of regulation of cell functionby this receptor. Finally recent data demonstrate that c-Met could beinvolved in tumor resistance to gefitinib or erlotinib suggesting thatcombination of compound targeting both EGFR and c-Met might be ofsignificant interest [Engelman J A at al., Science, 2007, 316:1039-43].

Greater than 20 mutations have been discovered within the c-met RTK [MaP. C. et al. Cancer and metastasis rev. 2003, 22:309-25]. The majorityof these mutations are missense mutations located in the intracellularpart of c-Met, within the tyrosine kinase domain and that can impairaffinity or binding properties therapeutic compounds targeting thistyrosine kinase domain. In that way, mutations of c-Met can be more orless responsive to therapeutic inhibitions. For example, in preclinicalstudies of SU11274 (small molecule tyrosine kinase inhibitor againstc-Met), certain mutations were distinguished to be sensitive andresistant to the action of this agent [Schmidt L. et al. Nat. Genet.1997, 16:68-73; Zhuang Z. et al. Nat. Genet. 1998, 20:66-9]. M1268T andH1112Y were sensitive mutations that showed decreased cell growth andmotility. Other mutations such as L1213V and Y1248 were found to beresistant to and unaffected by SU11274 [Hahn O. et al. Hematol OncolClin N Am. 2005, 19:343-67]. These studies demonstrate the direct impactof specific mutations on treatments targeting c-Met. However, anoligomerization of c-Met, in presence or in absence of the ligand, isrequired to regulate the binding affinity and the binding kinetics ofthe kinase toward ATP and tyrosine-containing peptide substrates [HaysJ. l., Watowich S J, Biochemistry. 2004, 43:10570-8].

In the past few years, many different strategies have been developed toattenuate c-Met signalling in cancer cell lines. These strategiesinclude i) neutralizing antibodies against c-Met or HGF/SF [Cao B, Su Y,Oskarsson M, Zhao P, Kort E J, Fisher R J, Wang L M, Vande Woude G F,Proc Natl Acad Sci USA. 2001, 98(13):7443-8; Martens T, Schmidt N O,Eckerich C, Fillbrandt R, Merchant M, Schwall R, Westphal M, Lamszus K,Clin Cancer Res. 2006, 12(20):6144-52] or the use of HGF/SF antagonistNK4 to prevent ligand binding to c-Met [Kuba K, Matsumoto K, Date K,Shimura H, Tanaka M, Nakamura T, Cancer Res., 2000, 60:6737-43], ii)small ATP binding site inhibitors to c-Met that block kinase activity[Christensen J G, Schreck R, Burrows J, Kuruganti P, Chan E, Le P, ChenJ, Wang X, Ruslim L, Blake R, Lipson K E, Ramphal J, Do S, Cui J J,Cherrington J M, Mendel D B, Cancer Res. 2003, 63:7345-55], iii)engineered SH2 domain polypeptide that interferes with access to themultidocking site and RNAi or ribozyme that reduce receptor or ligandexpression. Most of these approaches display a selective inhibition ofc-Met resulting in tumor inhibition and showing that c-Met could be ofinterest for therapeutic intervention in cancer.

Within the molecules generated for c-Met targeting, some are antibodies.

One of the most extensively described is the anti-c-Met 5D5 antibodygenerated by Genentech [WO96/38557] which behaves as a potent agonistwhen added alone in various models and as an antagonist when used as aFab fragment. Another antibody targeting c-Met is described by Pfizer asan antibody acting “predominantly as c-Met antagonist, and in someinstance as a c-Met agonist” [WO 2005/016382].

The inventor has demonstrated that the antibodies antagonists to c-Met,called 224G11, 227H1, 223C4 and 11E1, or functional fragment thereof,described herein and which have been also described in the patentapplications EP 07301231.2 filed on Jul. 12, 2007 and U.S. 61/020,639filed on Jan. 11, 2008, have the property to inhibit the c-Metdimerization and are active in vivo.

It can then be considered the problem to be solved by the invention asbeing the provision of a concrete, and not only a putative, combinationbeneficial for the treatment of cancer.

More particularly, it is an object of the invention to provide a noveland unexpected combination able to affect all the factors involved inthe c-Met activation as previously described.

In a general aspect, the invention relates to a method of treatment ofcancer in a mammal which comprises administering to said mammal atherapeutically effective amount of a combination of active componentscomprising an antagonist to c-Met and an aminoheteroaryl compound.

In another general aspect, the present invention is directed to acomposition comprising an antibody antagonist to c-Met, or a functionalfragment thereof, and an aminoheteroaryl compound, preferably for itsuse as a medicament.

The present invention is further directed to a pharmaceuticalcomposition comprising at least:

i) one antibody antagonist to c-Met, or a functional fragment thereof;and

ii) an aminoheteroaryl compound,

as combination products for simultaneous, separate or sequential use.

“Simultaneous use” is understood as meaning the administration of thetwo compounds of the composition according to the invention in a singleand identical pharmaceutical form.

“Separate use” is understood as meaning the administration, at the sametime, of the two compounds of the composition according to the inventionin distinct pharmaceutical forms.

“Sequential use” is understood as meaning the successive administrationof the two compounds of the composition according to the invention, eachin a distinct pharmaceutical form.

According to the invention, the combination is preferably mixed with anexcipient and/or a pharmaceutically acceptable vehicle.

It is also described and claimed a composition according to theinvention as a medicament.

In another embodiment, the combination of the invention may be in theform of a kit of parts. The invention therefore includes a productcontaining an antibody antagonist to c-Met, or one of these functionalfragments, and an aminoheteroaryl compound, preferably capable ofinhibiting the c-Met protein kinase activity as defined above, as acombined preparation for simultaneous, separate or sequential deliveryfor the treatment of cancer in a mammal in need thereof. In oneembodiment, a product contains an antibody antagonist to c-Met, or afunctional fragment thereof, and an aminoheteroaryl compound as definedabove as a combined preparation for simultaneous, separate or sequentialuse in treating a cancer in a mammal in need thereof.

In one embodiment, the invention provides a pharmaceutical packcontaining a course of an anti-cancer treatment for one individualmammal, wherein the pack contains (a) at least one unit of an antibodyantagonist to c-Met and (b) at least one unit of an aminoheteroarylcompound in unit dosage form.

In a more specific aspect, the invention deals with a method oftreatment of cancer in a mammal which comprises administering to saidmammal a therapeutically effective amount of the combination of activecomponents according to the present invention comprising an antibodyantagonist to c-Met, or functional fragment thereof, and anaminoheteroaryl compound.

In an also more specific aspect, the invention deals with a compositioncomprising an antibody antagonist to c-Met, or functional fragmentthereof, and an aminoheteroaryl according to the present invention forthe treatment of cancer, preferably in a mammal, more preferably inhuman. Said anti-cancer treatment comprises administering to said mammala therapeutically effective amount of the composition of the presentinvention. Preferably, said composition further comprises apharmaceutical acceptable carrier and/or excipient.

In a preferred embodiment, said aminoheteroaryl compound is capable ofinhibiting the c-Met protein kinase, More preferred are aminoheteroarylcompounds having at least 25%, preferably 40%, 50%, 60%, 75% and 85% ofthe c-Met protein kinase inhibiting activity demonstrated for theaminoheteroaryl compound named PF-02341066 in the same assay procedureconditions (see herein the complete structure of this PF-02341066compound).

Among the assay procedures which can be used to determine the level ofactivity of the c-Met protein kinase in presence of said aminoheroarylcompound, we can cite the procedure assay named “HGFR continuous-coupledspectrophotometric assay” described from page 100 in the PCT patentapplication published under the number WO 2006/021884.

The terms “antibody”, “antibodies” or “immunoglobulin” are usedinterchangeably in the broadest sense and include monoclonal antibodies(e.g., full length or intact monoclonal antibodies), polyclonalantibodies, multivalent antibodies or multispecific antibodies (e.g.,bispecific antibodies so long as they exhibit the desired bio logicalactivity).

More particularly, such molecule consists in a glycoprotein comprisingat least two heavy (H) chains and two light (L) chains inter-connectedby disulfide bonds. Each heavy chain is comprised of a heavy chainvariable region (or domain) (abbreviated herein as HCVR or VH) and aheavy chain constant region. The heavy chain constant region iscomprised of three domains, CH1, CH2 and CH3. Each light chain iscomprised of a light chain variable region (abbreviated herein as LCVRor VL) and a light chain constant region. The light chain constantregion is comprised of one domain, CL. The VH and VL regions can befurther subdivided into regions of hypervariability, termedcomplementarity determining regions (CDR), interspersed with regionsthat are more conserved, termed framework regions (FR). Each VH and VLis composed of three CDRs and four FRs, arranged from amino-terminus tocarboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3,CDR3, FR4. The variable regions of the heavy and light chains contain abinding domain that interacts with an antigen. The constant regions ofthe antibodies may mediate the binding of the immunoglobulin to hosttissues or factors, including various cells of the immune system (e.g.effector cells) and the first component (Clq) of the classicalcomplement system.

They may also include certain antibody functional fragments, asdescribed in greater detail herein, thereof which exhibit the desiredbinding specificity and affinity, regardless of the source orimmunoglobulin type (i.e., IgG, IgE, IgM, IgA, etc.).

In general, for the preparation of monoclonal antibodies or theirfunctional fragments, especially of murine origin, it is possible torefer to techniques which are described in particular in the manual“Antibodies” (Harlow and Lane, Antibodies: A Laboratory Manual, ColdSpring Harbor Laboratory, Cold Spring Harbor N.Y., pp. 726, 1988) or tothe technique of preparation from hybridomas described by Kohler andMilstein (Nature, 256:495-497, 1975).

By the expression “antagonist”, it must be understood a compound whichis capable of directly or indirectly, counteracting, reducing orinhibiting the biological activity of c-Met.

In general, a “therapeutically effective amount” refers to the minimumconcentrations or amounts of a compound or of compounds which areeffective to prevent, alleviate, reduce or ameliorate symptoms ofdisease or prolong the survival of the patient being treated. Moreparticularly, in reference to the treatment of cancer, a therapeuticallyeffective amount refers to that amount which has the effect of (1)reducing the size of (or preferably eliminating) the tumor; (2)inhibiting (that is, slowing to some extent, preferably stopping) tumormetastasis; (3) inhibiting to some extent (that is slowing to someextent, preferably stopping) tumor growth; and/or, (4) relieving to someextent (or preferably eliminating) one or more symptoms associated withthe cancer.

More particularly, said antibody antagonist to c-Met, or functionalfragment thereof, is selected from the group consisting of:

an antibody (derived from the 224G11 antibody), or a functional fragmentthereof, comprising a heavy chain containing CDR-H1, CDR-H2 and CDR-H3comprising respectively the amino acid sequences SEQ ID Nos. 1, 2 and 3;and a light chain containing CDR-L1, CDR-L2 and CDR-L3 comprisingrespectively the amino acid sequences SEQ ID Nos. 10, 11 and 12;

an antibody (derived from the 227H1 antibody), or a functional fragmentthereof, comprising a heavy chain containing CDR-H1, CDR-H2 and CDR-H3comprising respectively the amino acid sequences SEQ ID Nos. 4, 5 and 6;and a light chain containing CDR-L1, CDR-L2 and CDR-L3 comprisingrespectively the amino acid sequences SEQ ID Nos. 13, 11 and 14;

an antibody (derived from the 223C4 antibody), comprising a heavy chaincontaining CDR-H1, CDR-H2 and CDR-H3 comprising respectively the aminoacid sequences SEQ ID Nos. 7, 8 and 9; and a light chain containingCDR-L1, CDR-L2 and CDR-L3 comprising respectively the amino acidsequences SEQ ID Nos. 15, 16 and 17; and

an antibody (derived from the 11E1 antibody), comprising a heavy chaincontaining CDR-H1, CDR-H2 and CDR-H3 comprising respectively the aminoacid sequences SEQ ID Nos. 47, 48 and 49; and a light chain containingCDR-L1, CDR-L2 and CDR-L3 comprising respectively the amino acidsequences SEQ ID Nos. 50, 51 and 52.

In a more preferred embodiment, said antibody antagonist to c-Met, orfunctional fragment thereof, is selected from the group consisting of:

an antibody (derived from the 224G11 antibody), or a functional fragmentthereof, comprising a heavy chain comprising the amino acid sequence SEQID No. 18 and a light chain comprising the amino acid sequence SEQ IDNo. 21;

an antibody (derived from the 227H1 antibody), or a functional fragmentthereof, comprising a heavy chain comprising the amino acid sequence SEQID No. 19 and a light chain comprising the amino acid sequence SEQ IDNo. 22;

an antibody (derived from the 223C4 antibody), a heavy chain comprisingthe amino acid sequence SEQ ID No. 20 and a light chain comprising theamino acid sequence SEQ ID No. 23; and

an antibody (derived from the 11E1 antibody), comprising a heavy chaincomprising the amino acid sequence SEQ ID No. 53 and a light chaincomprising the amino acid sequence SEQ ID No. 54.

In another particular aspect, said antibody antagonist to c-Met, orfunctional fragment thereof, are recombinant, chimeric or humanizedantibody, or fragment thereof, derived from said 224G11, 227H1, 223C4 or11E1s antibody (derived is intended to designate the antibodies, orfragment thereof, comprising at least the 6 CDRs, or at least the lightand heavy chain as defined above for each of these antibodies).

More particularly, in a preferred embodiment, the present inventionrelates to a method or a composition according to the invention, whereinsaid antibody antagonist to c-Met is selected from 224G11, 227H1, 223C4and 11E1.

All these monoclonal antibodies were secreted by hybridomas deposited atthe CNCM on Mar. 14, 2007 under the numbers CNCM 1-3724 (correspondingto 11E1), I-3731 (corresponding to 224G11), 1-3732 (corresponding to227H1) and on Jul. 6, 2007 under the number 1-3786 (corresponding to223C4). These hybridomas consist in murine hybridoma resulting in thecellular fusion of immunized mouse splenocytes with a myeloma cell line(Sp20 Ag14).

By CDR regions or CDR(s), it is intended to indicate the hypervariableregions of the heavy and light chains of the immunoglobulins as definedby IMGT.

The IMGT unique numbering has been defined to compare the variabledomains whatever the antigen receptor, the chain type, or the species[Lefranc M.-P., Immunology Today 18, 509 (1997); Lefranc M.-P., TheImmunologist, 7, 132-136 (1999); Lefranc, M.-P., Pommié, C., Ruiz, M.,Giudicelli, V., Foulquier, E., Truong, L., Thouvenin-Contet, V. andLefranc, Dev. Comp. Immunol., 27, 55-77 (2003)]. In the IMGT uniquenumbering, the conserved amino acids always have the same position, forinstance cysteine 23 (1st-CYS), tryptophan 41 (CONSERVED-TRP),hydrophobic amino acid 89, cysteine 104 (2nd-CYS), phenylalanine ortryptophan 118 (J-PHE or J-TRP). The IMGT unique numbering provides astandardized delimitation of the framework regions (FR1-IMGT: positions1 to 26, FR2-IMGT: 39 to 55, FR3-IMGT: 66 to 104 and FR4-IMGT: 118 to128) and of the complementarity determining regions: CDR1-IMGT: 27 to38, CDR2-IMGT: 56 to 65 and CDR3-IMGT: 105 to 117. As gaps representunoccupied positions, the CDR-IMGT lengths (shown between brackets andseparated by dots, e.g. [8.8.13]) become crucial information. The IMGTunique numbering is used in 2D graphical representations, designated asIMGT Colliers de Perles [Ruiz, M. and Lefranc, M.-P., Immunogenetics,53, 857-883 (2002); Kaas, Q. and Lefranc, M.-P., Current Bioinformatics,2, 21-30 (2007)], and in 3D structures in IMGT/3Dstructure-DB [Kaas, Q.,Ruiz, M. and Lefranc, M.-P., T cell receptor and MHC structural data.Nucl. Acids. Res., 32, D208-D210 (2004)].

Three heavy chain CDRs and 3 light chain CDRs exist. The term CDR orCDRs is used here in order to indicate, according to the case, one ofthese regions or several, or even the whole, of these regions whichcontain the majority of the amino acid residues responsible for thebinding by affinity of the antibody for the antigen or the epitope whichit recognizes.

The following table 1 regroups elements concerning the preferredantibodies.

TABLE 1 224G11 227H1 223C4 11E1 I-3731 I-3732 I-3786 I-3724 Prot. Nucl.Prot; Nucl. Prot. Nucl. Prot. Nucl. SEQ ID SEQ ID SEQ ID SEQ ID SEQ IDSEQ ID SEQ ID SEQ ID CDR-H1 1 24 4 27 7 30 47 55 CDR-H2 2 25 5 28 8 3148 56 CDR-H3 3 26 6 29 9 32 49 57 H. chain 18 41 19 42 20 43 53 61CDR-L1 10 33 13 36 15 38 50 58 CDR-L2 11 34 11 34 16 39 51 59 CDR-L3 1235 14 37 17 40 52 60 L. chain 21 44 22 45 23 46 54 62

In another preferred embodiment of the method or the compositionaccording to the invention, said antibody antagonist to c-Met is theantibody, or one of these functional fragments, derived from theantibody called 224G11 (comprising at least the 6 CDRs SEQ ID Nos. 1, 2,3, 10, 11 and 12, or at least the SEQ ID Nos. 18 and 21).

As described in the patent application WO 2006/021884 published on Mar.2, 2006, (which teaching is incorporated in the present application byreference) aminoheteroaryl compounds are known as c-Met inhibitor andpresent protein tyrosine kinase activity.

As a surprising result, the applicant of the present application isshowing for the first time results illustrating a relevant synergy withthe combination of a monoclonal antibody antagonist to c-Met as abovedescribed with an aminoheteroaryl compound such as described in thepublished patent application WO 2006/021884.

The invention concerns a method of, or a composition for the treatmentof cancer in a mammal which comprises administering to said mammal atherapeutically effective amount of a combination of active componentscomprising at least an antibody antagonist to c-Met as above describedand an aminoheteroaryl compound, preferably selected from thosedescribed in the published patent application WO 2006/021884.

As preferred example, the aminoheteroaryl compound of the composition ofthe present invention consists in an enantiomerically pure compound offormula I

wherein:

Y is N or CR¹²;

R¹ is selected from hydrogen, halogen, C₆₋₁₂ aryl, 5-12 memberedheteroaryl, C₃₋₁₂ cycloalkyl, 3-12 membered heteroalicyclic,—O(CR⁶R⁷)_(n)R⁴, —C(O)R⁴, —C(O)OR⁴, —CN, —NO², —S(O)_(m)R⁴, —SO₂NR⁴R⁵,—C(O)NR⁴R⁵, —NR⁴C(O)R⁵, —C(═NR⁶)NR⁴R⁵, C₁₋₈ alkyl, C₂₋₈ alkenyl, andC₂₋₈ alkynyl; and each hydrogen in R¹ is optionally substituted by oneor more R³ groups;

R² is hydrogen, halogen, C C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C C₂₋₁₂ alkynyl,C. C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3-12 membered heteroalicyclic,5-membered heteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴, —NR⁴C(O)R⁵,—(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NC^(R)4R⁵, —C(═NR⁶)NR⁴R⁵,—NR⁴C(O)NR⁵R⁶, —NR⁴S(O)PR⁵ or —C(O)NR⁴R⁵, and each hydrogen in R² isoptionally substituted by R⁸;

each R³ is independently halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl 3-12 membered heteroalicyclic,5-12 membered heteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)2OR⁴, —NO₂,—NR⁴R⁵, —(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴,—NR⁴C(O)R⁵, —(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)OR⁴, —(CR⁶R⁷)_(n)C(O)NR⁴R⁵,—(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR⁶)NR⁴R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴S(O)PR⁵ or—C(O)NR⁴R⁵, each hydrogen in R³ is optionally substituted by R⁸, and R³groups on adjacent atoms may combine to form a C₆₋₁₂ aryl, 5-12 memberedheteroaryl, C₃₋₁₂ cycloalkyl or 3-12 membered heteroalicyclic group;

each R⁴, R⁵, R⁶ and R⁷ is independently hydrogen, halogen, C₁₋₁₂ alkyl,C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3-12membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R⁴,R⁵, R⁶ and R⁷ bound to the same nitrogen atom may, together with thenitrogen to which they are bound, be combined to form a 3 to 12 memberedheteroalicyclic or 5-12 membered heteroaryl group optionally containing1 to 3 additional heteroatoms selected from N, O, and S; or any two ofR⁴, R⁵, R⁶ and R⁷ bound to the same carbon atom may be combined to forma C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3-12 membered heteroalicyclic or 5-12membered heteroaryl group; and each hydrogen in R⁴, R⁵, R⁶ and R⁷ isoptionally substituted by R⁸;

each R⁸ is independently halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3-12 membered heteroalicyclic,5-12 membered heteroaryl, —NH₂, —CN, —OH, —O—C₁₋₁₂ alkyl,—O—(CH₂)_(n)C₃₋₁₂ cycloalkyl, —O—(CH₂)_(n)C₆₋₁₂ aryl, —O—(CH₂)_(n)(3-12membered heteroalicyclic) or —O—(CH2)_(n)(5-12 membered heteroaryl); andeach hydrogen in R⁸ is optionally substituted by R¹¹;

each R⁹ and R¹⁰ is independently hydrogen, halogen, C₁₋₁₂ alkyl, C₃₋₁₂cycloalkyl, C₆₋₁₂ aryl, 3-12 membered heteroalicyclic, 5-12 memberedheteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO2, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —NR⁴C(O)R⁵, —(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴S(O)PR⁵ or —C(O)NR⁴R⁵; R⁹ orR¹⁰ may combine with a ring atom of A or a substituent of A to four aC₃₋₁₂ cycloalkyl, 3-12 membered heteroalicyclic, C₆₋₁₂ aryl or 5-12membered heteroaryl ring fused to A; and each hydrogen in R⁹ and R¹⁰ isoptionally substituted by R³;

each R¹¹ is independently halogen, C₁₋₁₂ alkyl, C₁₋₁₂ alkoxy, C₃₋₁₂cycloalkyl, C₆₋₁₂ aryl, 3-12 membered heteroalicyclic, 5-12 memberedheteroaryl, —O—C₁₋₁₂, alkyl, —O—(C₁₋₂)_(n)C₃₋₁₂ cycloalkyl,—O—(CH₂)_(n)C₆₋₁₂ aryl, —O—(CH₂)_(n)(3-12 membered heteroalicyclic),—O—(CH₂)_(n)(5-12 membered heteroaryl) or —CN, and each hydrogen in R¹¹is optionally substituted by halogen, —OH, —CN, —C₁₋₁₂ alkyl which maybe partially or fully halogenated, —O—C₁₋₁₂ alkyl which may be partiallyor fully halogenated, —CO, —SO or —SO₂;

R¹² is hydrogen, halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl,C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3-12 membered heteroalicyclic, 5-12membered heteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂, —NR⁴R⁵,—(CR⁶R⁷)_(n)C(O)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴,—NR⁴C(O)R⁵, —(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR⁶)NR⁴R⁵,—NR⁴C(O)NR⁵R⁶, —NR⁴S(O)PR⁵ or —C(O)NR⁴R⁵, and each hydrogen in R¹² isoptionally substituted by R³;

each R¹³ is independently halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3-12 membered heteroalicyclic,5-12 membered heteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂,—NR⁴R⁵, —(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴,—NR⁴C(O)R⁵, —(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)OR⁴, —(CR⁶R⁷)_(n)C(O)NR⁴R⁵,—(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR⁶)NR⁴R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴S(O)PR⁵,—C(O)NR⁴R⁵, —(CR⁶R⁷)_(n)(3-12 membered heteroalicyclic),—(CR⁶R⁷)_(n)(C₃₋₁₂ cycloalkyl), —(CR⁶R⁷)_(n)(C₆₋₁₂ aryl),—(CR⁶R⁷)_(n)(5-12 membered heteroaryl), —(CR⁶R⁷)_(n)C(O)NR⁴R⁵, or—(CR⁶R⁷)_(n)C(O)R⁴, R¹³ groups on adjacent atoms may combine to form aC₆₋₁₂ aryl, 5-12 membered heteroaryl, C₃₋₁₂ cycloalkyl or 3-12 memberedheteroalicyclic group, and each hydrogen in R¹³ is optionallysubstituted by R³;

each m is independently 0, 1 or 2;

each n is independently 0, 1, 2, 3 or 4;

each p is independently 1 or 2;

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

In another preferred example, the said aminoheteroaryl compound consistsin an enantiomerically pure compound of formula Ia:

wherein:

Y is N or CH;

R¹ is a furan, thiopene, pyrrole, pyrroline, pyrrolidine, dioxolane,oxazole, thiazole, imidazole, imidazoline, imidazolidine, pyrazolepyrazoline, pyrazolidine, isoxazole, isothiazole, oxadiazole, triazole,thiadiazole, pyran, pyridine, piperidine, dioxane, morpholine, dithiane,thiomorpholine, pyridazine, pyrimidine, pyrazine, piperazine, triazine,trithiane, azitidine or phenyl group; and each hydrogen in R¹ isoptionally substituted by R³;

each R³ is independently halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3-12 membered heteroalicyclic,5-12 membered heteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂,—NR⁴R⁵, —(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)_(m)R⁴, —O(CR⁶R⁷)_(n)R⁴,—NR⁴C(O)R⁵, —(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)OR⁴, —(CR⁶R⁷)_(n)C(O)NR⁴R⁵,—(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR⁶)NR⁴R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴S(O)_(p)R⁵ or—C(O)NR⁴R⁵, each hydrogen in R³ is optionally substituted by R⁸, and R³groups on adjacent atoms may combine to form a C₆₋₁₂ aryl, 5-12 memberedheteroaryl, C₃₋₁₂ cycloalkyl or 3-12 membered heteroalicyclic group;

each R⁴, R⁵, R⁶ and R⁷ is independently hydrogen, halogen, C₁₋₁₂ alkyl,C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3-12membered heteroalicyclic, 5-12 membered heteroaryl; or any two of R⁴,R⁵, R⁶ and R⁷ bound to the same nitrogen atom may, together with thenitrogen to which they are bound, be combined to form a 3 to 12 memberedheteroalicyclic or 5-12 membered heteroaryl group optionally containing1 to 3 additional heteroatoms selected from N, O, and S; or any two ofR⁴, R¹, R⁶ and R⁷ bound to the same carbon atom may be combined to forma C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3-12 membered heteroalicyclic or 5-12membered heteroaryl group; and each hydrogen in R⁴, R⁵, R⁶ and R⁷ isoptionally substituted by R⁸;

each R⁸ is independently halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3-12 membered heteroalicyclic,5-12 membered heteroaryl, —NH₂, —CN, —OH, —O—C₁₋₁₂ alkyl,—O—(CH₂)_(n)C₃₋₁₂ cycloalkyl, —O—(CH₂)_(n)C₆₋₁₂ aryl, —O—(CH₂)_(n)(3-12membered heteroalicyclic) or —O—(CH₂)_(n)(5-12 membered heteroaryl); andeach hydrogen in R⁸ is optionally substituted by R¹¹;

each R⁹ and R¹⁰ is independently hydrogen, halogen, C₁₋₁₂ alkyl, C₃₋₁₂cycloalkyl, C₆₋₁₂ aryl, 3-12 membered heteroalicyclic, 5-12 memberedheteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO2, —NR⁴R⁵,—(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —NR⁴C(O)R⁵,—(CR⁶R⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)NCR⁴R⁵, —NR⁴C(O)NR⁵R⁶, —NR⁴S(O)PR⁵ or—C(O)NR⁴R⁵; R⁹ or R¹⁰ may combine with a ring atom of A or a substituentof A to form a C₃₋₁₂ cycloalkyl, 3-12 membered heteroalicyclic, C₆₋₁₂aryl or 5-12 membered heteroaryl ring fused to A; and each hydrogen inR⁹ and R¹⁰ is optionally substituted by R³;

each R¹¹ is independently halogen, C₁₋₁₂ alkyl, C₁₋₁₂ alkoxy, C₃₋₁₂cycloalkyl, C₆₋₁₂ aryl, 3-12 membered heteroalicyclic, 5-12 memberedheteroaryl, —O—C₁₋₁₂ alkyl, —O—(CH₂)_(n)C₃₋₁₂ cycloalkyl,—O—(CH₂)_(n)C₆₋₁₂ aryl, —O—(CH₂)_(n)(3-12 membered heteroalicyclic,—O—(C₁₋₁₂)_(n)(5-12 membered heteroaryl) or —CN, and each hydrogen inR¹¹ is optionally substituted by halogen, —OH, —CN, —C₁₋₁₂ alkyl whichmay be partially or fully halogenated, —O—C₁₋₁₂ alkyl which may bepartially or fully halogenated, —CO, —SO or —SO₂;

each R¹³ is independently halogen, C₁₋₁₂ alkyl, C₂₋₁₂ alkenyl, C₂₋₁₂alkynyl, C₃₋₁₂ cycloalkyl, C₆₋₁₂ aryl, 3-12 membered heteroalicyclic,5-12 membered heteroaryl, —S(O)_(m)R⁴, —SO₂NR⁴R⁵, —S(O)₂OR⁴, —NO₂,—NR⁴R⁵, —(CR⁶R⁷)_(n)OR⁴, —CN, —C(O)R⁴, —OC(O)R⁴, —O(CR⁶R⁷)_(n)R⁴,—NR⁴C(O)R⁵, —(CR⁶CR⁷)_(n)C(O)OR⁴, —(CR⁶R⁷)_(n)OR⁴,—(CR⁶R⁷)_(n)C(O)NR⁴R⁵, —(CR⁶R⁷)_(n)NCR⁴R⁵, —C(═NR⁶)NR⁴R⁵, —NR⁴C(O)NR⁵R⁶,—NR⁴S(O)PR⁵, —C(O)NR⁴R⁵, —(CR⁶R⁷)_(n)(3-12 membered heteroalicyclic),—(CR⁶R⁷)_(n)(C₃₋₁₂ cycloalkyl, —(CR⁶R⁷)_(n)(C₆₋₁₂ aryl),—(CR⁶R⁷)_(n)(5-12 membered heteroaryl), —(CR⁶R⁷)_(n)C(O)NR⁴R⁵, or—(CR⁶R⁷)_(n)C(O)R⁴, R¹³ groups on adjacent atoms may combine to form aC₆₋₁₂ aryl, 5-12 membered heteroaryl, C₃₋₁₂ cycloalkyl or 3-12 memberedheteroalicyclic group, and each hydrogen in R¹³ is optionallysubstituted by R³;

each m is independently 0, 1 or 2;

each n is independently 0, 1, 2, 3 or 4;

each p is independently 1 or 2;

or a pharmaceutically acceptable salt, hydrate or solvate thereof.

More particularly, preferred aminoheteroaryl compounds in the inventionare selected from aminopyridine or aminopyrazine compounds.

The said aminoheteroaryl compound is preferably, according to anembodiment of the invention, selected from the group consisting of5-Brom-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-ylamine;5-iodo-3-[(R)1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;5-bromo-3-[1(R)-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine;4-{5-Amino-6-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoicacid;(4-{5-Amino-6-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-phenyl)-piperazin-1-yl-methanone;4-(4-{5-Amino-6-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-benzoyl)-piperazine-1-carboxylicacid ter-butyl ester;3-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[4-(piperazin-i-ylcarbonyl)phenyl]pyridin-2-anine;4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3-yl}-N-[2-(dimethylamino)ethyl]-N-methylbenzamide;(4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3-yl}phenyl)methanol;(4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3-yl}-N-[3-(dimethylamino)propyl]-N-methylbenzamide;tert-butyl4-(4-{6-amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]pyridin-3-yl}benzoyl)piperazine-1-carboxylate;3-[(R)-1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-pyridin-2-ylamine;1-[4-(4-{6-Amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidin-1-yl]-2-hydroxy-ethanone;3-[(R)-1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine;3-[(R)-1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine;3-[(R)-1-(2,6-Dichloro-3-fluoro-phenyl-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyrazin-2-ylamine;3-[(R)-1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1H-pyrazol-4-yl)-pyrazin-2-ylamine:1-[4-(4-{5-Amino-6-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyrazol-1-yl)-piperidin-1-yl]-2-hydroxy-ethanone;3-[(R)-1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-[1-(1-methyl-piperidin-4-yl)-1H-pyrazol-4-yl]-pyrazin-2-ylamine;1-[4-(4-{5-Amino-6-[(R)-1-2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyrazin-2-yl}-pyrazol-1-yl)-piperidin-1-yl]-2-dimethylamino-ethanone;3-[(R)-1-(2-Chloro-3,6-difluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)pyridin-2-ylamine;or a pharmaceutically acceptable salt, solvate or hydrate thereof.

In another preferred embodiment of the invention, the aminoheteroarylcompound is a3-[(R)-1-(2,6-Dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine.Another name given to this chemical compound is PF-02341066 (alsowritten PF-2341066).

This particular compound is described in details in Example 13 of thepublished patent application WO 2006/021884 and the process for itspreparation is described in procedure 62 which is cited below.

General Procedure 62:

To a solution of5-bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine(12.83 g, 33.76 mmol) in anhydrous DMF (100 mL) was added di-tert-butyldicarbonate (21.25 g, 97.35 mmol) and 4-dimethylami[pi]opyridine (0.793g, 6.49 mmol). The reaction was stirred at ambient temperature for 18hours under nitrogen. To the mixture was added saturated NaHCd₃ solution(300 mL), and extracted with EtOAc (3×250 mL). The combined extractswere washed with water (5×100 mL), sat. NaHCO₃, and brine, then driedover Na2SO4. After filtration, evaporation, and high vacuum drying,di-boc protected5-bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylaminewas obtained as an off-white foam solid (19.59 g, 100% yield). ¹H NMR(DMSO-d₆, 400 MHz) δ 8.18 (d, 1H), 7.83 (d, 1H), 7.59 (dd, 1H), 7.48 (t,1H), 6.25 (q, 1H), 1.75 (d, 3H), 1.39 (s, 9H), 1.19 (s, 9H).

To a solution of the di-boc protected5-bromo-3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-2-ylamine(19.58 g, 33.76 mmol) in DMSO (68 mL) was added potassium acetate (11.26g, 114.78 mmol) and bis(pinacolato)diboron (10.29 g, 40.51 mmol). Themixture was degassed and charged with nitrogen three times, thenPd(dppf)CI₂.CH₂CI₂ (1.38 g, 1.69 mmol) was added. The reaction mixturewas degassed and charged with nitrogen three times, and then stirred at80° C. oil bath under nitrogen for 12 hours. The reaction was cooled toambient temperature, diluted with ethyl acetate (100 mL), and filteredthrough a celite pad which was washed with ethyl acetate. The combinedethyl acetate solution (700 mL) was washed with water (5×100 mL), brine(100 mL), and dried over Na₂SO₄. After filtration and concentration, theresidue was purified on a silica gel column eluting with EtOAc/Hexane(0%-50%) to provide di-boc protected3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamineas a foam sold (20.59 g, 97% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 8.20(d, 1H), 7.70 (d, 1H), 7.63 (dd, 1H) 1 7.47 (t, 1H), 6.20 (q, 1H), 1.73(d, 3H), 1.50-1.13 (m, 30H).

To a solution of di-boc protected3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine(20.34 g, 32.42 mmol) in CH₂CI₂ (80 mL) was added a solution of dry HClin dioxane (4N, 40.5 mL, 162 mmol). The reaction solution was stirred at40° C. oil bath under nitrogen for 12 hours. The reaction mixture wascooled to ambient temperature, diluted with EtOAc (400 mL), then washedcarefully but quickly with saturated NaHCO₃ until the water layer wasbasic (pH>8). The organic layer was washed with brine, and dried overNa₂SO₄. After filtration, evaporation, and high vacuum drying,3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine was obtained as an off-white foamsolid (13.48 g, 97% yield). ¹H NMR (DMSO-d₆, 400 MHz) δ 8.01 (d, 1H),7.27 (dd, 1H), 7.17 (d, 1H), 7.03 (t, 1H), 6.12 (q, 1H), 5.08 (bs, 2H),1.81 (d, 3H), 1.30 (s, 6H), 1.28 (s, 6H).

To a stirred solution of3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine(4.2711 g, 10.0 mmol) and4-(4-bromo-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester(3.9628 g, 12.0 mmol) in DME (40 mL) was added a solution of Na₂CO₃(3.1787 g, 30.0 mmol) in water (10 mL). The solution was degassed andcharged with nitrogen three times. To the solution was addedPd(PPh₃J₂CI₂ (351 mg, 0.50 mmol). The reaction solution was degassed andcharged with nitrogen again three times. The reaction solution wasstirred at 87° C. oil bath for about 16 hours (or until consumption ofthe borane pinacol ester), cooled to ambient temperature and dilutedwith EtOAc (200 mL). The reaction mixture was filtered through a pad ofcelite and washed with EtOAc. The EtOAc solution was washed with brine,dried over Na₂SO₄, and concentrated. The crude product was purified on asilica gel column eluting with EtOAc/hexane system (0% EtOAc to 100%EtOAc) to afford4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylicacid tert-butyl ester (3.4167 g, 65% yield, −95% purity) with a Rf of0.15 (50% EtOAc/Hexanes). MS m/e 550 (M+1)⁺.

To a solution of4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylicacid tert-butyl ester (566.7 mg, 1.03 mmol) in methanol (5 mL) ordichlorometha[pi]e (30 mL) was added 4N HCI/dioxane (15 mL). Thesolution was stirred for about 1 hour or until the de-protection wascomplete. The solvents were evaporated and the residue was dissolved inmethanol and purified on a reversed phase C-18 preparative HPLC elutingwith acetonitrile/water with 0.1% acetic acid from 5% to 30% with alinear gradient. After lyophilization,3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamineacetate was obtained as a white solid (410 mg, 78% yield, 100% HPLCpurity, 96.4% ee). ¹H NMR (DMSO-d₆, 400 MHz) δ 7.84 (s, 1H), 7.68 (d,1H), 7.50 (dd, 1H), 7.46 (s, 1H), 7.37 (t, 1H), 6.83 (d, 1H), 6.02 (q,1H), 5.57 (bs, 2H), 4.09 (m, 1H), 2.98 (m, 2H), 2.53 (m, 2H), 1.88 (m,2H), 1.82 (s, 3H), 1.73 (d, 3H), 1.70 (m, 2H). MS m/e 450 (M+1)⁺.

In a particular aspect of the invention, it is envisaged a compositionof the present invention wherein said aminoheteroaryl compound is thecompound of formula Ib:

In another aspect, the invention concerns a method wherein said canceris selected from cancers overexpressing c-Met and/or displaying anauto-phosphorylated c-Met.

More particularly, said cancer is selected from prostate cancer,osteosarcomas, lung cancer, breast cancer, endometrial cancer,glyoblastoma or colon cancer.

In a preferred embodiment, the invention relates to a composition asabove mentioned, wherein said antibody antagonist to c-Met is selectedfrom the 224G11, 227H1, 223C4 and 11E1 derived antibodies, or from thefunctional fragments thereof.

More particularly, the said antibody antagonist to c-Met is derived fromthe 224G11 antibody.

Still in another embodiment of the invention, it is described herein acomposition, wherein said aminoheteroaryl compound is selected fromaminopyridine or aminopyrazine compounds.

More particularly, the said aminoheteroaryl compound is the compound offormula Ib:

The invention also relates to the use of a composition as defined in thepresent application for treating cancer in a mammal.

In a particular preferred embodiment, said cancer is selected fromcancers overexpressing c-Met and/or displaying an auto-phosphorylatedc-Met. More particularly, said cancer is selected from prostate cancer,osteosarcomas, lung cancer, breast cancer, endometrial cancer,glyoblastoma or colon cancer.

The invention will be better understood at the reading of the followingexamples wherein:

FIG. 1 illustrates the in vivo activity of 224G11 and the in vivoactivity of PF-2341066 on NCI-H441 NSCLC, and

FIG. 2 illustrates the synergic in vivo activity of a combination of224G11 and PF-2341066 on NCI-H441 NSCLC.

EXAMPLE 1 In Vivo Activity of 224G11 and PF-02341066 as SingleTreatments

In order to verify that the NCI-H441 in vivo model available in thelaboratory is sensible to both the 224G11 antibody and the PF-2341066compound, immunocompromised mice engrafted subcutaneously with NCI-H441were used. Briefly, NCI-H441 NSCLC cells from ATCC were cultured in RPMI1640 medium, 10% FCS, 1% L-Glutamine. Cells were split two days beforeengraftment so that they were in exponential phase of growth. Tenmillion NCI-H441 cells were injected s.c. to Athymic nude mice. Fivedays after implantation, tumors were measurable and animals were dividedinto groups of 6 mice with comparable tumor size. For the antibodytreatment, mice were treated i.p. with a loading dose of 2 mg of 224G11Mab/mouse and then twice a week with 1 mg of antibody/mouse. 50 mg/kg ofPF-02341066 was administered p.o. (oral gavage), daily for a week andthen 5 days a week with a double dose the fifth day. Treatment lastedduring the whole experiment. Tumor volume was measured twice a week andcalculated by the formula: π/6×length×width×height.

Results described in FIG. 1 showed a significant difference in tumorsgrowth of mice treated both with 224G11 and PF-02341066. In thisexperiment 224G11 and PF2341066 showed comparable antitumoralactivities.

EXAMPLE 2 In Vivo Activity of a Combination of 224G11 and PF-02341066

NCI-H441 cells from ATCC were routinely cultured in RPMI 1640 medium,10% FCS, 1% L-Glutamine. Cells were split two days before engraftment sothat they were in exponential phase of growth. Ten million NCI-H441cells were engrafted to Athymic nude mice. Five days after implantation,tumors were measurable and animals were divided into groups of 6 micewith comparable tumor size. For the antibody treatment, mice weretreated i.p. with a loading dose of 2 mg of 224G11 Mab/mouse and thentwice a week with 1 mg of antibody/mouse. 50 mg/kg of PF-2341066 wasadministered p.o. (oral gavage), daily for a week and then 5 days a weekwith a double dose the fifth day. The group of mice receiving both224G11 and PF-2341066 was treated following the same modalities as theone described above for each compound. Tumor volume was measured twice aweek and calculated by the formula: π/6×length×width×height and animalweights were monitored every day over the period of treatment.

Statistical analysis was performed at each measured time using aMann-Whitney test. In this experiment, mice of the control group weresacrificed on day 53 for ethical reasons. At day 53 post firstinjection, the average tumor volume of single modality treated groups isreduced by 64%, 73% and 93% for 224G11, PF-2341066 and 224G11+PF-2341066respectively. At Day 53, the combined therapy improved significantlytumor growth compared to single therapy treatments (p≦0.002 compared toPF-2341066 alone and p≦0.002 compared to 224G11 alone), 1 out of 6 micebeing without tumor in the combined therapy group. No significantdifferences were observed between the 2 single modality treatment.

These results, represented at FIG. 2, were confirmed 14 days after theend of treatments (D67) where tumor volume of the group receiving thecombination therapy remained significantly lower than the ones injectedwith the single modality treatment and where 16% of mice receiving thecombined treatment were still tumor free.

1. A composition comprising an antibody antagonist to c-Met, or afunctional fragment thereof, and an aminoheteroaryl compound.
 2. Acomposition according to claim 1 as a medicament.
 3. A pharmaceuticalcomposition comprising at least: i) one antibody antagonist to c-Met, ora functional fragment thereof; and ii) an aminoheteroaryl compound, ascombination products for simultaneous, separate or sequential use. 4.The composition according to one of claims 1 to 3, wherein said antibodyantagonist to c-Met, or functional fragment thereof, is selected fromthe group consisting of: an antibody, or a functional fragment thereof,comprising a heavy chain containing CDR-H1, CDR-H2 and CDR-H3 comprisingrespectively the amino acid sequences SEQ ID Nos. 1, 2 and 3; and alight chain containing CDR-L1, CDR-L2 and CDR-L3 comprising respectivelythe amino acid sequences SEQ ID Nos. 10, 11 and 12; an antibody, or afunctional fragment thereof, comprising a heavy chain containing CDR-H1,CDR-H2 and CDR-H3 comprising respectively the amino acid sequences SEQID Nos. 4, 5 and 6; and a light chain containing CDR-L1, CDR-L2 andCDR-L3 comprising respectively the amino acid sequences SEQ ID Nos. 13,11 and 14; an antibody, or a functional fragment thereof, comprising aheavy chain containing CDR-H1, CDR-H2 and CDR-H3 comprising respectivelythe amino acid sequences SEQ ID Nos. 7, 8 and 9; and a light chaincontaining CDR-L1, CDR-L2 and CDR-L3 comprising respectively the aminoacid sequences SEQ ID Nos. 15, 16 and 17; and an antibody, or afunctional fragment thereof, comprising a heavy chain containing CDR-H1,CDR-H2 and CDR-H3 comprising respectively the amino acid sequences SEQID Nos. 47, 48 and 49; and a light chain containing CDR-L1, CDR-L2 andCDR-L3 comprising respectively the amino acid sequences SEQ ID Nos. 50,51 and
 52. 5. The composition according to one of claims 1 to 4, whereinsaid antibody antagonist to c-Met, or functional fragment thereof, isselected from the group consisting of: an antibody, or a functionalfragment thereof, comprising a heavy chain comprising the amino acidsequence SEQ ID No. 18 and a light chain comprising the amino acidsequence SEQ ID No. 21; an antibody, or a functional fragment thereof,comprising a heavy chain comprising the amino acid sequence SEQ ID No.19 and a light chain comprising the amino acid sequence SEQ ID No. 22;an antibody, or a functional fragment thereof, comprising the amino acidsequence SEQ ID No. 20 and a light chain comprising the amino acidsequence SEQ ID No. 23; and an antibody, or a functional fragmentthereof, comprising a heavy chain comprising the amino acid sequence SEQID No. 53 and a light chain comprising the amino acid sequence SEQ IDNo.
 54. 6. The composition according to one of claims 1 to 5, whereinsaid antibody antagonist to c-Met, or functional fragment thereof, isselected from the group consisting of the monoclonal antibodies secretedby the hybridomas deposited at the Collection Nationale de Cultures deMicroorganismes (CNCM, Institut Pasteur, Rue du Docteur Roux, Paris,France) on Mar. 14, 2007 under the numbers I-3724, I-3731, I-3732 and onJul. 6, 2007 under the number I-3786.
 7. The composition according toclaim 6, wherein said antibody antagonist to c-Met is the monoclonalantibody called 224G11 secreted by the hybridoma deposited at CNCM onMar. 14, 2007 under the number I-3731, or antibody, or functionalfragment thereof, derived from said 224G11 antibody comprising: at leastthe 6 CDRs having the sequences SEQ ID Nos. 1, 2, 3, 10, 11 and 12; orat least the heavy chain comprising the amino acid sequence SEQ ID No.18 and a light chain comprising the amino acid sequence SEQ ID No. 21.8. The composition according to one of claims 1 to 7, wherein saidaminoheteroaryl compound is selected from aminopyridine or aminopyrazinecompounds.
 9. The composition according to one of claims 1 to 8, whereinsaid aminoheteroaryl compound is the compound of formula Ib:


10. Composition according to one of the claims 1 to 9 for treatingcancer.
 11. The use of a pharmaceutical composition of claim 3,comprising as combination products for simultaneous, separate orstaggered use at least the antibody antagonist to c-Met, or a functionalfragment thereof, and an aminoheteroaryl compound as defined in one ofclaims 4 to 9, for preparing a drug to treat cancer.
 12. Compositionaccording to claim 10 or use according to claim 11, wherein said canceris selected from cancers overexpressing c-Met and/or displaying anauto-phosphorylated c-Met.
 13. Composition according to claim 10 or useaccording to claim 11, wherein said cancer is selected from prostatecancer, osteosarcomas, lung cancer, breast cancer, endometrial cancer,glyoblastoma or colon cancer.
 14. Composition according to one of theclaims 10, 12 and 13, or use according to one of the claims 11 to 13 fortreating cancer in a mammal, preferably human.